ArticleOncotarget2014
Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression.
Article in Oncotarget, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 73 citations in OpenAlex.
- Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2017 · on this mapTrial
- NEK2 promotes trastuzumab resistance in gastric cancer through WTAP/YTHDF1-dependent m6A regulation of FN1.Molecular biology reports · 2026Article
- HER2 targeted therapy resistance in breast cancer: from molecular landscape to clinical aspects.Science China. Life sciences · 2026Review
- Article
- The Overexpression of Myelin and Lymphocyte Protein (MAL) Downregulates MUC1 and Enhances Cisplatin Sensitivity in Non-Small Cell Lung Cancer Cells.Journal of Cancer · 2026Article
- Synergistic anticancer effects of Chrysin and trastuzumab in HER2-Positive breast cancer cells.Scientific reports · 2025Article
- Metabolic hallmarks of trastuzumab resistance.Expert opinion on therapeutic targets · 2025Review
- α-hederin Targets USP5 to Inhibit Colorectal Tumorigenesis by Disrupting STAT3 Deubiquitination.International journal of biological sciences · 2025Article
- Review
- Review
- Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer.Journal of translational medicine · 2024Article
- STAT3 Pathways Contribute to β-HCH Interference with Anticancer Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2024Article
- Targeting C21orf58 is a Novel Treatment Strategy of Hepatocellular Carcinoma by Disrupting the Formation of JAK2/C21orf58/STAT3 Complex.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery.Journal of experimental & clinical cancer research : CR · 2024Review
- Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition.International journal of molecular sciences · 2023Review
- Resistance to Trastuzumab.Cancers · 2022Review
- Direct knockdown of phospho-PTM targets mediated by TRIM21 can improve personalized treatment in breast cancer.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Galectin-3 enhances trastuzumab resistance by regulating cancer malignancy and stemness in HER2-positive breast cancer cells.Thoracic cancer · 2022Article
- MUC1 is a potential target to overcome trastuzumab resistance in breast cancer therapy.Cancer cell international · 2022Review
- Resistance to endocrine therapy in HR + and/or HER2 + breast cancer: the most promising predictive biomarkers.Molecular biology reports · 2022Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.